Biology subjects

Santos, V.

Publications and source records attributed to Santos, V..

6 recordsLinked to original sources

bioRxiv2026

NGFR-driven suppression of antigen presentation limits CD8+ T cell immunity and response to checkpoint blockade

Immune checkpoint blockade has revolutionized cancer therapy; however, numerous tumors remain resistant by adopting cellular states that impede immune recognition. In this study, we identify the nerve growth factor receptor (NGFR) as a regulator of immune evasion in head and neck squamous cell carcinoma (HNSCC). Genetic ablation of Ngfr resulted in impaired tumor growth in immunocompetent MOC2 HNSCC, while pharmacological inhibition with THX-B reduced primary tumor growth and spontaneous metastatic dissemination. Single-cell profiling of MOC2 tumors demonstrated that Ngfr loss redirected tumor cells away from invasive EMT-like states and enhanced antigen-processing and presentation programs. This was accompanied by increased presentation of tumor antigens and expansion of effector CD8+ T-cells in vivo. Functionally, CD8+ T-cell depletion, Batf3 deficiency, and JAK1/2 inhibition restored the growth of Ngfr-deficient tumors, indicating that NGFR loss exposes tumors to CD8+ T-cell-mediated control through a JAK-associated antigen-presentation program. Notably, NGFR blockade sensitized otherwise resistant MOC2 tumors to anti-PD1 therapy, and the combination of THX-B with anti-PD1 significantly improved tumor control and survival. In human HNSCC, spatial profiling revealed that NGFR+ tumor regions exhibited reduced HLA-DR expression and limited CD3+ T-cell infiltration. Notably, an NGFR-associated antigen-presentation signature stratified survival and response in HNSCC patients undergoing immune checkpoint blockade. Interestingly, this signature was also linked to improved outcomes in melanoma patients. We also observed a significant increase in the effector CD8+ T-cell fraction in melanoma NGFR KO tumors linked to a significant decrease in tumor growth. These findings position NGFR as a regulator of tumor immune visibility and support NGFR inhibition as a strategy to enhance immunotherapy response.

cancer biology↗

bioRxiv2026

Nerve growth factor receptor identifies a basal subpopulation linked to poor prognosis and reduced immunotherapy responses in bladder cancer

PurposeBladder cancer (BLCA) is a heterogeneous tumor type. Only one third of muscle-invasive (MIBC) patients respond to immune checkpoint inhibitors (ICIs). Reliable resistance markers are needed to guide clinical decisions. We investigated the nerve growth factor receptor (NGFR) in BLCA and analyzed its correlation with disease progression and response to immunotherapy. Experimental DesignWe analyzed NGFR expression in BLCA cell lines, organoids, mouse models and patient samples. The cohorts used were The Cancer Genome Atlas (TCGA), enriched in muscle-invasive bladder cancer (MIBC) (n=407); IMvigor210, representing MIBC patients treated with ICIs (n=348); and UROMOL2, as a non-muscle-invasive bladder cancer (NMIBC)-specific cohort (n=535). IMvigor010 was also included (n=728). Patients were stratified by NGFR expression quartiles. We analyzed survival and tumor subtypes and performed stromal deconvolution and functional profiling. We assessed stemness- and invasion-related features in SCaBER cells. ResultsNGFR marks a basal tumor cell subcluster and is independently associated with poor prognosis in TCGA and IMvigor210. NGFR-high tumors show stromal content enriched in cancer-associated fibroblasts, lower neoantigen burden, higher CD8+ T effector signature together with an immune-excluded phenotype, and a CAF-specific TGF{beta} signature. In the immunotherapy-treated cohort, high NGFR expression was also associated with poorer outcome. Functionally, NGFR appears to promote a stem-like/pro-invasive program in BLCA cells. ConclusionsNGFR identifies a basal-like BLCA subpopulation linked to poor survival, while its association with immunotherapy response requires further validation. In addition, our in vitro analyses support a role of NGFR in stem-like and invasive traits, highlighting its relevance as a biomarker in BLCA.

cancer biology↗

bioRxiv2023

NGFR regulates germinal center B-cell activation and negative selection

The expression of the Nerve growth factor receptor (NGFR) has been described in follicular dendritic cells (FDCs), the major lymphoid stromal cell (LSC) compartment regulating B-cell activation within germinal centers (GCs). However, the role of NGFR in humoral response is not well defined. In this work, we have studied the effect of Ngfr KO in LNs organization and function. Ngfr KO led to spontaneous GC formation and expansion of GC B-cell compartment which were related to Ngfr depletion in non-hematopoietic radioresistant compartment. In agreement, Ngfr KO mice showed alterations in LSC with an increased frequency of FDCs harboring an activated phenotype characterized by the overexpression of CD21/35, MAdCAM-1, and VCAM-1. Moreover, Ngfr KO mice showed GC ectopic location, loss of polarization, impaired high-affinity antibody production, and increased circulating autoantibodies. In addition, Ngfr KO/Bcl2 Tg mice displayed increased levels of autoantibodies, higher incidence of autoimmunity, and decreased overall survival. Our work shows that NGFR maintains GC structure and functionality, being involved in the regulation of antibody production and immune tolerance.

immunology↗

bioRxiv2022

Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis

PurposeMalignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive softtissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-{beta} coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. Experimental DesignENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathways and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. ResultsENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST tumor growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Importantly, combination of anti-ENG therapy with MEK inhibition reduced more effectively tumor cell growth and angiogenesis. ConclusionsOur data unveil a tumor-promoting function of ENG in MPNSTs and support the combined use of anti-ENG antibodies and MEK inhibitors as a novel potential combination to control MPNSTs growth and metastasis. Statement of translational relevanceMalignant peripheral nerve sheath tumors (MPNSTs) present a poor clinical outcome due to tumor aggressiveness and the absence of effective treatments that underline the need for identifying novel therapeutic approaches. Here, we show that ENG is upregulated in human MPNSTs and we uncover an important role for this coreceptor in MPNST. ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST tumor growth and metastasis in xenograft models, supporting a novel use of anti-ENG therapies for MPNST treatment. Currently, MEK inhibitors are used in the clinic to shrink peripheral nerve sheath tumors (e.g. plexiform neurofibromas). Importantly, we demonstrate that combination of anti ENG antibodies with MEK inhibitors efficiently blocked MPNST growth and metastasis. Our findings provide a rationale for combining anti-ENG and MEK inhibitors as a new strategy for MPNST management.

cancer biology↗

bioRxiv2022

Deficiency in pericyte remodeling as a basis for impaired capillary flow and structure during brain aging

Deterioration of brain capillary flow and architecture is a hallmark of aging and dementia. It remains unclear how loss of brain pericytes in these conditions contributes to capillary dysfunction. Here, we conduct cause-and-effect studies by optically ablating pericytes in adult and aged mice in vivo. Focal pericyte loss induces capillary dilation without blood-brain barrier disruption. These abnormal dilations are exacerbated in the aged brain, and result in increased flow heterogeneity in capillary networks. A subset of affected capillaries experience reduced perfusion due to flow steal. Some capillaries stall in flow and regress, leading to loss of capillary connectivity. Remodeling of neighboring pericytes restores endothelial coverage and vascular tone within days. Pericyte remodeling is slower in the aged brain, resulting in regions of persistent capillary dilation. These findings link pericyte loss to disruption of capillary flow and structure. They also identify pericyte remodeling as a therapeutic target to preserve capillary flow dynamics.

neuroscience↗

bioRxiv2018

Differential Gene Expression Analysis of a Small Colony Variant of Escherichia coli K-12

As persistent residents of planktonic bacterial cultures, small colony variants (SCVs) constitute a slow-growing subpopulation with atypical colony morphology and unusual biochemical characteristics that, in the case of clinical isolates, cause latent and recurrent infections. We propose a novel blueprint for the formation of E. coli SCVs through DNA microarray analysis, coupled with complete genome sequencing and verification by qRT-PCR. While others have used DNA microarrays to study quorum sensing in E. coli SCVs, our work represents the first proposal for a combination of novel mutations, amplified by a differential shift in expression of select gene groups that work in concert to establish and maintain the SCV phenotype. This combination of genetic and expression events fall under selective pressure, leading to unequal fitness in our strain, SCV IH9 versus its parental strain, BW7261 (a MG1655 descendant). We hypothesize that this combination of events would ordinarily be lethal for bacteria, but instead confers a survival advantage to SCV IH9 due to its slow growth and resistance to acidic and oxidative stress challenges.

molecular biology↗